PROJECT C: HT, Mammographic Densities and Breast Cancer. There is growing epidemiologic, experimental, and clinical evidence that hormone therapy with estrogen and progestin (EPT) for menopausal women increases the risk of breast cancer more than estrogen treatment alone. Results from the Women's Health Initiative clinical trial strongly confirmed this. However, a number of clinically important issues remain to be solved, in particular to determine which women are at highest risk of breast cancer if they use EPT. Only a subset of women develop mammographic density change when they start EPT. Since mammographic density is an important breast cancer predictor, it is important to determine whether this subset of women are the ones who will develop breast cancer as a result of EPT, and if so, what the determinants, including the genetic determinants, of the mammographic density changes are. Obvious candidate genes are those that encode enzymes important in metabolism, transport, and transactivation activity of EPT. We have previously found that changes in serum estrone levels predict mammographic density changes in women randomized to EPT. We also have some pilot evidence suggesting that genetic factors associated with increases in hormone levels may predict who will develop such mammographic density increase. This proposed project will expand on these early findings. We are proposing a genetic epidemiologic study that takes advantage of the ongoing California Teachers Study (CTS), a cohort of teachers and administrators in California that have relatively uniform health coverage and high mammographic screening rates. The primary specific aims of this project are to determine whether selected variants in genes encoding for enzymes important in metabolism, transport, or activity of EPT predict 1) mammographic density increases in women who commence EPT treatment after menopause and 2) breast cancer risk. The secondary aims are to determine 3) whether these genetic variants predict breast cancer risk in EPT users and 4) the risk of breast cancer associated with increased mammographic density following start of EPT use. Aim 1 will be assessed in a cohort of teachers from CTS of 1000 EPT starters, while aims 2-4 will be addressed in a nested case-control study from CTS with approximately 900 breast cancer cases and 900 controls. If successful, this proposal could have large clinical implications as it could help us to understand who can safely use EPT in terms of breast cancer susceptibility.